Hypoxia occurs in 90% of solid tumors and is strongly associated with an increased propensity for metastasis. Hypoxia induces tumor progression largely through inducing HIF-mediated transcription, resulting in alterations to tumor cell metabolism, as well as increases in migration and invasion. Hypoxia also results in a myriad of changes to the tumor microenvironment (TME). While many studies have examined the immediate effects of hypoxia on tumor cells and the associated TME, far fewer have focused on the long-term consequences of transient reductions in oxygen. In this issue of Cancer Research, Iriondo and colleagues examined whether short-term exposure to hypoxia leads to a “hypoxic memory” in the context of breast cancer. The authors used established cell lines and circulating tumor cell lines to demonstrate that these cells harbor a hypoxic memory that sustains downregulation of IFN signaling and antigen presentation (AP) pathways that contribute to tumor progression via alterations to tumor cells and the TME. The authors further showed that cells that have experienced hypoxia maintain the reduction in IFN signaling in vivo and are more aggressive. They determined that the hypoxic memory and reduction of IFN signaling can be reversed with a histone deacetylase inhibitor, entinostat, providing a potential means to reverse hypoxia-induced suppression of IFN signaling. As suppression of IFN signaling has the potential to influence both tumor cells and the TME, the identification of a strategy to inhibit long-term suppression of IFN signaling downstream of hypoxia could prove to be an effective means to target tumor progression. See related article by Iriondo et al., p. 3141

中文翻译：

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记住缺氧：揭示短暂缺氧对 IFN 信号传导和乳腺癌进展的长期影响


90% 的实体瘤都会出现缺氧，并且与转移倾向的增加密切相关。缺氧主要通过诱导 HIF 介导的转录来诱导肿瘤进展，从而导致肿瘤细胞代谢的改变以及迁移和侵袭的增加。缺氧还会导致肿瘤微环境（TME）发生多种变化。虽然许多研究已经研究了缺氧对肿瘤细胞和相关 TME 的直接影响，但很少有研究关注氧气短暂减少的长期后果。在本期《癌症研究》中，Iriondo 及其同事研究了短期缺氧是否会导致乳腺癌患者出现“缺氧记忆”。作者使用已建立的细胞系和循环肿瘤细胞系来证明这些细胞具有低氧记忆，可维持 IFN 信号传导和抗原呈递 (AP) 途径的下调，从而通过改变肿瘤细胞和 TME 促进肿瘤进展。作者进一步表明，经历缺氧的细胞在体内维持 IFN 信号传导的减少，并且更具攻击性。他们确定，组蛋白脱乙酰酶抑制剂恩替司他可以逆转缺氧记忆和干扰素信号传导的减少，从而提供了逆转缺氧诱导的干扰素信号传导抑制的潜在方法。由于抑制 IFN 信号传导有可能影响肿瘤细胞和 TME，因此确定长期抑制缺氧下游 IFN 信号传导的策略可能被证明是靶向肿瘤进展的有效手段。参见 Iriondo 等人的相关文章，第 17 页。 3141